Association of HLA-restricted HERV-derived peptide-related cytotoxic T-lymphocyte induction and sex bias in therapeutic responses in gastric cancer: Secondary Analysis of Data from 3 Randomized Trials and an Observational Study from 1977 to 2011

Introduction: Whether human leukocyte antigens (HLAs) and human endogenous retroviruses (HERVs) affect therapeutic outcomes is unknown. Here, we focused on the similarity between HERV and human immunodeficiency virus (HIV) genes. Methods: By comparing training and validation sets in pooled 2,049 gastric cancers, we evaluated the significance of baseline HLA examination in clinical treatment response. HLA-restricted CD8 + cytotoxic T-lymphocyte (CTL) epitopes on HERV and HIV genes were predicted using bioinformatics. HLA-restricted putative HERV peptides were selected based on the similarity of HLA-restricted HIV peptides. Changes in CD8 + cells were compared at baseline and 1 year after gastrectomy. Results: We identified 53 fully recovering subjects who received effective therapies in the validation set, based on the HLA of 101 patients who received effective therapies in the training set. We found putative 84 HERV-derived peptides that might have induced HLA-restricted CTL by administering therapies in 2041 subjects. We identified 155 subjects, whose CD8 + cells increased significantly after administering therapies in only females (paired t -tests, P = .005), resulting in significantly better survival compared with CTL (-) patients (hazard ratio [HR], 5.05; 95% CI, 3.42 to 8.92; P < .0001 [female: HR, 8.46; 95% CI, 3.15 to 22.72; P < .0001, male: HR, 3.89; 95% CI, 2.20 to 6.88; P < .0001]). All CTL (+) females received effective therapy and CTL (+) unclassified patients survived during the follow-up period. Conclusions: We confirmed the clinical significance of HLA. Research on HLA-restricted HERV gene-derived peptides may reveal the central mechanism of sex bias in therapeutic responses.